As disclosed in U.S. Pat. No. 3,600,437 (Marshall), it is known that 2-(3-phenoxybenzene)propionic acid--commonly known as fenoprofen--and related compounds are pharmaceutically-active materials that can be prepared by the techniques taught in that patent. Those techniques have the disadvantage of being tedious and time-consuming, as well as using starting materials that are not as economical and readily-available as might be desired.
It is known that nitrobenzene acetic acids and their nitriles are particularly useful intermediates for the synthesis of pharmaceuticals. For example, 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]propionic acid--an anti-inflammatory and analgesic agent commonly known as indoprofen--can be prepared from a 2-(4-nitrobenzene)propionic acid intermediate by hydrogenating the intermediate, reacting the resultant 2-(4-aminobenzene)propionic acid with phthalic anhydride, and reducing the resultant 2-(4-phthalimidophenyl)propionic acid, e.g., with zinc and formic acid. Also, 2-(4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]butyric acid--commonly known as indobufen--can be formed in a similar manner from 2-(4-nitrobenzene)butyric acid, and 2-(3-phenoxybenzene)propionic acid--commonly known as fenoprofen--can be synthesized from 2-(4-nitro-3-phenoxybenzene)propionic acid.
In the past, a disadvantage of employing nitrobenzene acetic acids or nitriles as pharmaceutical intermediates has been the difficulty of preparing those intermediates by conventional techniques. For example, 2-(4-nitrobenzene)propionic acid has been customarily formed by a three-step procedure wherein (1) 4-ethylnitrobenzene is reacted with sodium phenoxide and carbon dioxide to produce disodium 2-methyl-2-(4-nitrobenzene)malonate, (2) the malonate salt is converted by acidification into the corresponding diacid, and (3) the diacid is heated to effect decarboxylation.
It would obviously be a welcome contribution to the art to provide a method of synthesizing nitrobenzeneacetonitriles, including nitrophenoxy- or nitrophenylthiobenzeneacetonitriles, and derivatives thereof in a simple, straightforward manner.